Novel cyclin D1-based DC vaccine inhibits TNBC tumor growth

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis after the failure of standard chemotherapeutic regimens. Immunotherapies activating the patient’s own immune system to fight various types of cancer are emerging as a powerful alternative and complement to standard chemotherapy and radiation therapy. Since dendritic cells (DCs) regulate every aspect of adaptive immune responses, we sought to generate DC vaccines that target TNBC. Recently, we found that targeting CD40 on DCs induced superior anti-tumor cytotoxic T cell responses compared to targeting other DC receptors. In the quest to find tumor-specific (overexpressed) antigens, we recently identified the cell cycle protein, cyclin D1, as a potential antigen for a DC-targeting-based vaccine against TNBC. Cyclin D1 is overexpressed in many tumors, including TNBC, and we found that cyclin D1-specific effector T cells could be readily expanded from the blood of TNBC patients or normal human donors. To test whether targeting cyclin D1 to DCs through CD40 can control tumor growth, we implemented a novel TNBC mouse model in our laboratory. This consists of a transgenic mouse expressing human CD40 in a C57BL/6 background and a recently characterized syngeneic EO771-LMB metastatic breast cancer cell line with TNBC characteristics. We found that in a therapeutic setting, targeting cyclin D1 (highly conserved between mice and humans) to DCs through CD40 led to significant inhibition of tumor growth in mice. Thus, these data suggest that cyclin D1-based DC-targeting vaccines could be a novel immunotherapeutic candidate for TNBC.